Project Summary: Manganese (Mn) is an essential metal for human health, but exposure to excess levels can cause neurological disease. Emerging evidence suggests that long-term exposures to low levels of anthropogenic or environmental sources of Mn may have detrimental effects on human neurological health. Automobile combustion of gasoline containing methylcyclopentadienyl manganese tricarbonyl (MMT) has the potential to significantly increase Mn exposures to human populations where this fuel additive is used. However, there is a paucity of knowledge on the neurological health effects of chronic exposures to low-levels of Mn. While moderate to high levels of Mn exposure are associated with motor abnormalities and cognitive dysfunction as well as basal ganglia dopaminergic dysfunction in humans and non-human primates. The extent to which lower levels of Mn exposure may target specific cognitive domains and alter brain chemistry is not known. The studies described in this application are the result of a unique and productive on-going collaboration of scientists with expertise in behavioral neuroscience, molecular imaging, molecular and cellular neuroscience, neurotoxicology, neurochemistry and neuropathology applying the latest state-of-the-art behavioral and neuroimaging modalities to understand the behavioral dysfunction and underlying molecular and cellular mechanisms of Mn-induced neurological disease in the living non-human primate brain. Our most recent evidence suggests that chronic Mn exposure in non-human primates produces in vivo neurochemical changes resembling those in schizophrenia. Further, exposure to Mn produces a cellular stress response and diffuse amyloid-[unreadable] plaques in the frontal cortex resembling those in the aging brain and in Alzheimer[unreadable]s disease. These preliminary findings provide a putative link of an environmental toxicant (Mn) to mental and neurological disease. The proposed studies will expand on these findings and provide the most comprehensive assessment to date on the neurological consequences of chronic Mn exposure on the non-human primate brain. The knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population. Relevance: The work that we describe in this proposal will define the behavioral, in vivo neurochemistry and neuropathological effects of chronic low level Mn exposure in non-human primates. They represent the most comprehensive assessment to date on the neurological consequences of chronic exposure to levels of Mn that segments of the population are likely to encounter in their environment. The knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population.